tbuckley/cabot-search huggingface dataset:
Blood transcriptomic signature in type-2 biomarker-low severe asthma and asthma control
Authors: Xue Zeng, Jing Qing, Chi-Ming Li, Jiamiao Lu, Tracy Yamawaki, Yi-Hsiang Hsu, Bryan Vander Lugt, Hailing Hsu, John Busby, P.J. McDowell, David J. Jackson, Ratko Djukanovic, John G. Matthews, Joseph R. Arron, Peter Bradding, Christopher E. Brightling, Rekha Chaudhuri, David F. Choy, D. Cowan, S.J. Fowler, Timothy C. Hardman, Tim Harrison, Peter Howarth, James Lordan, A.H. Mansur, Andrew Menzies-Gow, Ian D. Pavord, Samantha Walker, Ashley Woodcock, Liam G. Heaney
Journal: Journal of Allergy and Clinical Immunology (2023)

Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids.We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker-high/-low patients with severe asthma to relate transcriptomic signatures to T2 biomarkers and asthma symptom scores.Bulk RNA-seq data were generated for blood samples (baseline, week 24, week 48) from 301 participants recruited to a randomized clinical trial of corticosteroid optimization in severe asthma. Unsupervised clustering, differential gene expression analysis, and pathway analysis were performed. Patients were grouped by T2-biomarker status and symptoms. Associations between clinical characteristics and differentially expressed genes (DEGs) associated with biomarker and symptom levels were investigated.Unsupervised clustering identified 2 clusters; cluster 2 patients were blood eosinophil-low/symptom-high and more likely to be receiving oral corticosteroids (OCSs). Differential gene expression analysis of these clusters, with and without stratification for OCSs, identified 2960 and 4162 DEGs, respectively. Six hundred twenty-seven of 2960 genes remained after adjusting for OCSs by subtracting OCS signature genes. Pathway analysis identified dolichyl-diphosphooligosaccharide biosynthesis and assembly of RNA polymerase I complex as significantly enriched pathways. No stable DEGs were associated with high symptoms in T2-biomarker-low patients, but numerous associated with elevated T2 biomarkers, including 15 that were upregulated at all time points irrespective of symptom level.OCSs have a considerable effect on whole blood transcriptome. Differential gene expression analysis demonstrates a clear T2-biomarker transcriptomic signature, but no signature was found in association with T2-biomarker-low patients, including those with a high symptom burden.
TRLS-11. A PHASE 1 STUDY OF SAVOLITINIB IN RECURRENT, PROGRESSIVE, OR REFRACTORY MEDULLOBLASTOMA, HIGH-GRADE GLIOMA, DIFFUSE INTRINSIC PONTINE GLIOMA, AND CENTRAL NERVOUS SYSTEM (CNS) TUMORS HARBORING MET ABERRATIONS: A PEDIATRIC BRAIN TUMOR CONSORTIUM TRIAL
Authors: Ralph Salloum, Jie Huang, Clinton F Stewart, Christine Fuller, Teresa Smolarek, Alicia Lenzen, Angela J Waanders, Patiricia Baxter, Holly Lindsay, Nathan Robison, Natasha Pillay-Smiley, Sonia Partap, Jason Fangusaro, Arzu Onar-Thomas, Maryam Fouladi, Ira J Dunkel
Journal: Neuro-Oncology (2023)

Abstract Aberrant mesenchymal epithelial transition receptor (MET) activation leads to neoplasia, promotes invasive tumor growth, angiogenesis, and metastasis. Deregulation of MET signaling pathway is frequently observed in pediatric CNS tumors making MET inhibition a potential therapeutic target in this patient population. A phase 1 first-in-children trial of the MET inhibitor savolitinib was performed in children with recurrent, progressive or refractory medulloblastoma, high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), and other CNS tumors harboring MET aberrations. The study sought to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of savolitinib using a Rolling-6 design given orally once daily continuously, and to describe its toxicity profile and pharmacokinetics (PK). Once the MTD was established, a PK expansion cohort was opened to enrollment. This will be followed by an efficacy expansion cohort for patients whose tumors harbor activating genomic MET aberrations. Tumor tissue and blood were collected as part of correlative studies in consenting subjects. Twenty-eight patients enrolled (median age:12 years; range: 6-21); one patient was deemed ineligible, and 22 patients were evaluable for dose finding. The MTD/RP2D was 350 mg/m2 (dose level 3). Two dose limiting toxicities were reported in 2 subjects and consisted of grade 3 fatigue and grade 3 ALT elevation. The most common grade 3/4 toxicities were: neutropenia (7.7%) and lymphopenia (7.7%). One partial response was observed in a patient with recurrent HGG on dose level 1 (150 mg/m2). As of the most recent data freeze, the patient had completed 35 treatment courses. Sustained stable disease was experienced by 3 other patients with recurrent DIPG who remained on treatment for a median of 9 cycles (range: 4-24). Correlative studies are ongoing and will be presented. Savolitinib was well-tolerated in children with recurrent CNS tumors with an MTD/RP2D of 350 mg/m2. Antitumor activity was observed.
Influence of Food With Different Fat Concentrations on Alectinib Exposure: A Randomized Crossover Pharmacokinetic Trial
Authors: Daan A.C. Lanser, Simon P. de Leeuw, Esther Oomen-de Hoop, Peter de Bruijn, Marthe S. Paats, Daphne W. Dumoulin, Stijn L.W. Koolen, Anne-Marie C. Dingemans, Ron H.J. Mathijssen, G.D. Marijn Veerman
Journal: Journal of the National Comprehensive Cancer Network (2023)

Alectinib is the keystone treatment in advanced anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC). An exposure-response threshold of 435 ng/mL has recently been established, albeit 37% of patients do not reach this threshold. Alectinib is orally administered, and absorption is largely influenced by food. Hence, further investigation into this relationship is needed to optimize its bioavailability.In this randomized 3-period crossover clinical study in ALK+ NSCLC, alectinib exposure was compared among patients with different diets. Every 7 days, the first alectinib dose was taken with either a continental breakfast, 250-g of low-fat yogurt, or a self-chosen lunch, and the second dose was taken with a self-chosen dinner. Sampling for alectinib exposure (Ctrough) was performed at day 8, just prior to alectinib intake, and the relative difference in Ctrough was compared.In 20 evaluable patients, the mean Ctrough was 14% (95% CI, -23% to -5%; P=.009) and 20% (95% CI, -25% to -14%; P<.001) lower when taken with low-fat yogurt compared with a continental breakfast and a self-chosen lunch, respectively. Administration with a self-chosen lunch did not change exposure compared with a continental breakfast (+7%; 95% CI, -2% to +17%; P=.243). In the low-fat yogurt period, 35% of patients did not reach the threshold versus 5% with the other meals (P<.01).Patients and physicians should be warned for a detrimental food-drug interaction when alectinib is taken with low-fat yogurt, because it results in a clinically relevant lower alectinib exposure. Intake with a self-chosen lunch did not change drug exposure and could be a safe and patient-friendly alternative.
HGG-01. INFANT-TYPE HEMISPHERIC GLIOMA: NEW MOLECULAR ALTERATIONS AND PRECISION-MEDICINE TREATMENT
Authors: Wanming Hu, Li Yuan, Jing Zeng
Journal: Neuro-Oncology (2023)

Abstract Introduction Infant-type hemispheric glioma, harboring alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET, is a new subtype of Pediatric-type diffuse high-grade gliomas in the 2021 WHO classification of CNS tumors. It has important clinical therapeutic value with specialized therapeutic drugs. Here, we presented 3 cases of infant-type hemispheric glioma. Patient1 with EML4-ALK fusion which often appeared in lung cancer, the other 2 patients have new molecular alterations which has not been reported before (Patient2 has both NTRK1-TP53/TP53-NTRK1 fusions and p53 protein showed characteristic cytoplasm positive; Patient3 presented a brand-new ALK-QKI fusion combined with ALK mutation and focal SMARCB1 deletion. All these 3 cases received corresponding targeted therapy and have a good recovery and normal neurologic function till now. Methods Immunohistochemistry. Fluorescent in situ hybridization. Whole-transcriptome sequencing. Results Case 1: 8 months, male, right semiovale center occupation. HISTOPATHOLOGY High-grade neuroepithelial neoplasm. IHC: GFAP (only few cells+), Olig2(-), S100(+), CD56(+), Syn(-), NSE(focal+), NeuN(-), CD34(-), INI-1(+), Ki67(10%+). Characteristic Molecular Information: EML4-ALK fusion. Follow-up: 15 months, alive. Case 2: 3 years, female, insular lobe occupation. HISTOPATHOLOGY Gliosarcoma. IHC: GFAP(partly+), Olig2(partly+), Vimentin(+), P53(cytoplasm+), pan-TRK(+), Ki67(25%+). Reticular fiber staining showed biphasic tissue pattern with reticulin-rich sarcomatous and reticulin-free gliomatous elements. Characteristic Molecular Information: NTRK1-TP53 and TP53-NRTK1 fusion. Follow-up: 27 months, alive. Case 3: 3 years, male, left parietal occipital lobe occupation. HISTOPATHOLOGY GBM and AT/RT. IHC: GFAP(partly+), Olig2(partly+), INI-1(partly-), BRG1(+), SYN(-), CD34(-), BRAF(-), S100(-), CK(-), H3K27M(-), IDH1(-), P53(40%+), ATRX(+), pan-TRK(-), ALK(+), Ki67(30%+). Characteristic Molecular Information: ALK mutation, ALK-QKI fusion, RAD51C mutation and focal SMARCB1(INI-1) deletion. Follow-up: 14 months, alive. Conclusion: Infant-type hemispheric glioma is a special kind of glioma, which is particularly suitable for precision-medicine treatment approaches. Their overall survival is good compared with other three pHGG subtype.
OUTC-08. IMPLEMENTING SOCIAL DETERMINANT OF HEALTH DATA COLLECTION FOR PEDIATRIC, ADOLESCENT AND YOUNG ADULT NEURO-ONCOLOGY PATIENTS IN THE CLINICAL TRIAL CONSORTIA SETTING: PROGRESS AND CHALLENGES
Authors: Vidya Puthenpura, Kira Bona, Tab Cooney, Scott Coven, Tom Davidson, Maryam Fouladi, Cassie Kline, Sarah Leary, Sabine Mueller, Adam Green, Asher Marks
Journal: Neuro-Oncology (2023)

Abstract Adverse social determinants of health (SDoH) are associated with decreased survival and increased long-term complications amongst pediatric and adolescent and young adult (AYA) neuro-oncology patients. These outcome disparities are in part due to inferior access to clinical trials and comprehensive, multidisciplinary care. SDoH including food insecurity, housing instability, inability to pay for utilities, and personal safety issues have been shown to negatively impact therapy adherence and exacerbate survival disparities. As such, efforts to improve health equity must include evaluating and addressing SDoH at diagnosis. Existing literature has been limited by a reliance on proxy measures of adverse SDOH such as neighborhood or census area-level socioeconomic status data, which poorly reflect individual circumstances. There is a complex interplay between neighborhood and personal socioeconomic status that has not been extensively studied and is poorly understood. In addition, socioeconomic status is only one component of SDoH. No validated tool currently exists to assess SDoH amongst pediatric and AYA cancer patients. It is imperative that multicenter clinical trials collect SDoH data to inform both trial design and interpretation of results. These data will be important to understanding and identifying patterns in tumor and toxicity incidence, as well as understanding the burden on families in adhering to trial therapies. Based on our previous work, we will present the importance of incorporating SDoH data collection within the clinical trial consortia setting. In addition, we will review the development of a comprehensive SDoH questionnaire and discuss facilitators and barriers to the incorporation of SDoH questionnaires into multicenter clinical trials and offer solutions based on our experience.
DIPG-53. LSD1 DEGRADATION SYNERGIZES WITH HDAC INHIBITION IN PEDIATRIC H3K27M DIFFUSE MIDLINE GLIOMA
Authors: Rebecca Haase, Andrew Groves, Hafsa Mire, Jun Qi, Mariella Filbin
Journal: Neuro-Oncology (2023)

Abstract H3K27M-mutated diffuse midline glioma (H3K27M DMG) is an aggressive, lethal pediatric brain tumor which resists conventional cancer treatments. To identify new therapeutic targets, our lab executed a focused CRISPR negative selection screen in patient-derived H3K27M cell lines after treatment with the histone deacetylase (HDAC) inhibitor panobinostat, and discovered a strong co-dependence with the histone demethylase LSD1. We further explored the therapeutic potential of this synergistic interaction with a screen of HDAC- and LSD1- targeting drugs to identify synergistic combinations, which show penetration of the blood brain barrier suitable for clinical translation. Interestingly, conventional catalytic LSD1 inhibitors did not seem to synergize with HDAC inhibitors tested on cell viability, while a recently described CoREST/LSD1 degrader phenocopied the effects seen in our CRISPR screen. We hypothesized that the CoREST/LSD1 degrader induces synergy with HDAC inhibitors through elimination of a scaffolding function of LSD1. To prove this, we knocked out LSD1 using CRISPR/Cas9 in H3K27M cells and subsequently treated with a panel of HDAC inhibitors. These showed a significant sensitization compared to controls cells. Further, we confirm the high specificity of the CoREST/LSD1 degrader by performing streptavidin bead pull down with a newly synthesized biotin-conjugated probe. This revealed that it interacts with the entire CoREST complex (members include LSD1, RCOR1, HDAC1/2). In conclusion, we show that degrading CoREST/LSD1 in combination with HDAC inhibition is a synergistic strategy in H3K27M DMG. For future translational studies, we will assess biomarkers upon treatment and analyse compound potency in vivo.
BIOL-13. DEPLOYING NEW MODELS OF NF-1 MUTANT LOW GRADE GLIOMA TO ACCELERATE THERAPEUTIC DEVELOPMENT
Authors: Lujain Alaali, Jinchong Xu, Jeff Mumm, Ming Yuan, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2023)

Abstract Pediatric low grade glioma (pLGG) research is hampered by a paucity of genetically accurate cell line models and xenografts. To address this need, we have developed and characterized multiple in vivo and organoid models. We used cell reprogramming conditions (CRC) to establish and propagate JHH-NF1-PA1, a NF1-mutant line derived from a low grade optic pathway glioma of a patient with type 1 neurofibromatosis. JHH-NF1-PA1 cells persist and take up midline positions when xenografted into the brains of zebrafish, allowing testing of therapeutics in vivo. We developed a human iPSC-brain organoid system comprising of midline neurons, glia, and microglia, largely recapitulating the microenvironment of midline low grade glioma. Our JHH-NF1-PA1 cells incorporate into these brain organoids, allowing us to test potential therapeutics in an in vitro setting in which the tumor cells grow in the appropriate microenvironment. We have also further defined the mouse BL6 NF1 null glioma cell line 1810, which forms orthotopic xenografts in mice. This last model will be useful for therapeutic testing in a syngeneic BL6 background, allowing assessment of immune infiltration and signaling downstream of NF1 loss and potential immunotherapeutics. Together, these in vitro and in vivo models of NF1-driven low grade glioma make an important contribution to our understanding of the biology of low grade glioma.
DIPG-04. TUMOR CELL-INTRINSIC TIM-3 PROMOTES DIFFUSE INTRINSIC PONTINE GLIOMA TUMORIGENESIS
Authors: Iker Ausejo-Mauleon, Virginia Laspidea, Daniel de la Nava, Sara Nuin, Daniel Palacios-Alonso, Javier Marco-Sanz, Oren Becher, Li Jiang, Mariella G Filbon, Fernando Pastor, Marta M Alonso
Journal: Neuro-Oncology (2023)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor and the leading cause of pediatric death caused by cancer. Despite great strides in the understanding of this disease, the median overall survival is still dismal. TIM-3 is emerging as an alternative to the classic immune checkpoints CTLA-4 and PD-1, and its expression regulates by various mechanisms the function of innate and adaptative immunity. In our work, we demonstrated that TIM-3 is expressed in murine and human DIPG tumor cell lines in vitro and in vivo. TIM-3 knockout using CRISPR/Cas9 was lethal in all human DIPG cell lines evaluated. However, a doxycycline-inducible shRNA-TIM-3 significantly reduced the proliferation of DIPG human cell lines (100% control vs. 25% shRNA TIM-3). Additionally, TIM-3KO murine cell lines displayed a significant decrease in clonogenicity, proliferation, and migration in vitro compared with parental DIPG murine cell lines. Interestingly, loss of TIM-3 expression did not result in cell death, as shown by the evaluation of apoptosis. In vivo evaluation of TIM-3KO cell lines tumorigenicity demonstrated that mice bearing TIM3-KO cells had an overall median survival (35 days) significantly higher than the ones bearing the control guide cells (16 days). RNAseq data indicated that TIM-3 plays a critical role in DIPG murine cells tumorigenesis and survival through the MAPK signaling pathway. Finally, single-cell sequencing and immunochemistry of human tumor samples uncovered TIM-3 expression in patients. TIM-3 expression in DIPG tumor cells correlated with genes positively involved in regulating ion transport, IL-6 production, and response to IFN-γ pathways. We also observed enrichment in genes regulating MAPK and ERK1/ERK2 cascades in these patients. Collectively, these data suggest that TIM-3 expression might have a role in the survival and tumorigenesis of DIPG cells.
BIOL-10. MOUSE MODELING OF PEDIATRIC MYCN GLIOMA REVEALS INTRATUMORAL HETEROGENEITY INCLUDING NEURONAL AND OLIGODENDROGLIAL LINEAGE SIGNATURES
Authors: Melanie Schoof, Shweta Godbole, Thomas K Albert, Matthias Dottermusch, Carolin Walter, Annika Ballast, Nan Qin, Marlene Baca Olivera, Carolin Göbel, Sina Neyazi, Dörthe Holdhof, Catena Kresbach, Gefion Dorothea Epplen, Vanessa Thaden, Mirjam Blattner-Johnson, Franziska Modemann, Ann-Kristin Afflerbach, Alicia Eckhardt, Daniel Muenter, Nina Struve, David T W Jones, Marc Remke, Julia E Neumann, Kornelius Kerl, Ulrich Schüller
Journal: Neuro-Oncology (2023)

Abstract Pediatric glioma of the subclass MYCN are highly aggressive tumors with a median age at diagnosis of 8 years and a median survival of only 14 months. Molecularly, they frequently carry MYCN amplifications, TP53 mutations or both of these alterations. Due to their rarity, such tumors have only recently been identified as a distinct entity, and both biological as well as clinical details have not been fully addressed. In order to further investigate the biology and treatment options of these tumors, preclinical models are urgently needed. Therefore, we generated a genetically engineered model by breeding hGFAP-cre::Trp53Fl/Fl::lsl-MYCN mice, which carry a loss of Trp53 and show aberrant MYCN expression in neural precursors of the central nervous system. All such mice developed aggressive forebrain tumors early in lifetime that mimic their human counterparts regarding histology, DNA methylation, and gene expression. Single cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. To find new treatment options, we performed in vitro high-throughput drug screening on both, mouse and human tumor cells. Among 640 investigated anticancer compounds, Doxorubicin, Irinotecan, and Etoposide effectively suppressed the growth of tumor cells. As FDA-approved chemotherapeutics, these compounds are used for the treatment of other pediatric brain tumors. Repurposing them for the treatment of MYCN-driven high grade glioma could achieve a rapid transition to glioma treatment. We believe that our model will pave the way to improved treatment strategies for patients with these highly aggressive tumors.
DIPG-41. EXPLORING BRAIN PENETRANT PEPTIDE-DRUG CONJUGATES IN DIFFUSE INTRINSIC PONTINE GLIOMA MODELS
Authors: Jasmine Clark, Samuel McKinnon, Jorge_Luis JImenez-Macias, Edward Miller, Andrei Loas, Brad Pentelute, Rishi Lulla, Sean Lawler
Journal: Neuro-Oncology (2023)

Abstract The blood brain barrier (BBB) tightly controls access of molecules to the brain, limiting the efficacy of therapeutics for diseases of the central nervous system. We recently developed a novel approach for drug delivery across the BBB using a perfluoroaryl macrocyclic peptide-drug conjugate, M13-Pt(IV). This approach showed accumulation of platinum (Pt) within the brain, and improved survival in murine xenograft models using adult patient-derived glioblastoma cells. We also found that uptake of M13-Pt(IV) into tumor tissue is further enhanced by 6-bromo-indirubin acetoxime (BIA), a small molecule with anti-invasive properties. Because diffuse intrinsic pontine glioma (DIPG) is an invasive brain tumor protected from systemic drugs by an intact BBB, we hypothesized that this approach may be of particular benefit in this tumor type. Therefore our goal here was to investigate peptide-mediated drug delivery across the BBB in DIPG, using M13-Pt(IV) as a tool compound. When tested across a panel of four distinct DIPG lines in vitro the M13-Pt(IV) conjugate showed tumor cell killing effects superior to Pt(IV). BIA significantly slowed DIPG cell migration and lowered endothelial cell permeability in vitro via reduced expression of tight junction proteins as shown by immunostaining and decrease in trans-endothelial resistance. Bi-weekly dose regimens of M13-Pt(IV) are well-tolerated in nude mice at a dose of 15mg/kg, 3-fold more than the reported tolerable cisplatin dose at 5 mg/kg. Moreover, in vivo BIA also enhanced drug M13-Pt(IV) uptake into adult glioblastoma tumors. In vivo uptake and efficacy studies in DIPG tumor-bearing mice are underway. Overall, our data using a prototype peptide-drug conjugate support the further development of BBB-crossing peptide-drug conjugates for DIPG. Identification of the optimal therapeutic combinations for clinical application is our focus for future studies.